Potential mechanism of action (MOA) for Acthar Gel (repository corticotropin injection)*

What is Acthar Gel?

Acthar Gel is a naturally sourced complex mixture of adrenocorticotropic hormone analogues and other pituitary peptides.1

How is Acthar Gel believed to work?

Acthar Gel engages melanocortin receptors (MCRs) expressed on immune, organ, and tissue cells throughout the body and is thought to produce both an indirect anti-inflammatory effect and a direct cell modulation effect.2-6

*While the exact mechanism of action of Acthar Gel is unknown, further investigation is being conducted. This information is based on nonclinical data and the relationship to clinical benefit is unknown.

*While the exact mechanism of action of Acthar Gel is unknown, further investigation is being conducted. This information is based on nonclinical data and the relationship to clinical benefit is unknown.

Acthar Gel engages receptors on the adrenal cortex to secrete free cortisol at levels slightly above normal endogenous range, producing a potential indirect anti-inflammatory effect7,8

Chart showing free cortisol response after a single therapeutic dose

Acthar Gel AUC24=324 ± 61 h*ng/mL

The prednisone-equivalent range of normal endogenous cortisol is 5 mg–7.5 mg.8

This information is based on pharmacodynamic data and the relationship to clinical benefit is unknown.

After 5 doses of 80 U twice per week, Acthar Gel's prednisone-equivalent daily cortisol exposure above normal endogenous range is between 1.3 mg and 3.8 mg of prednisone.7,8

Pharmacodynamic studies: These data are from an independent study in healthy adult subjects.7 Data presented are following a single dose given on the first day.

Study design: An open-label, single-center, randomized, multiple-dose, parallel-group study to compare the pharmacodynamics (PD) and safety of intermittent doses of Acthar Gel to daily oral methylprednisolone (MP) in healthy subjects. Subjects between 18 and 50 years old were randomized to receive Acthar Gel 40 U or 80 U subcutaneously twice weekly for 15 days (n=12/group) or 16 mg of oral MP given once daily for 15 days (n=12), followed by a tapering regimen of 8 mg daily for 2 days, then 4 mg daily for 2 days. The most frequently reported treatment emergent adverse events (TEAEs) that occurred in 2 or more subjects were (in decreasing order of frequency): injection site hemorrhage, headache, injection site erythema, injection site pruritus, insomnia, acne, infrequent bowel movements, and injection site pain. All TEAEs experienced during this study were considered mild in severity.7

Study limitations: As this was a healthy-subject, open-label study with no placebo control, the clinical relevance of differences in tolerability is unknown and remains to be investigated for patient populations.7

Acthar Gel has shown a direct modulatory effect on B cells, independent of cortisol release

In an in vitro study using human B cells, Acthar Gel reduced B-cell proliferation and IgG production independent of cortisol release.3,10

 
Chart showing the effect of Acthar Gel on B cells
Chart showing the effect of Acthar Gel on B cells
 

P<0.05 versus vehicle-treated group.

This information is based on nonclinical data and the relationship to clinical benefit is unknown.

Study design: The effects of Acthar Gel on human B-lymphocyte function in vitro were evaluated using highly purified B-cell populations cultured in the absence of glucocorticoids and stimulated by recombinant IL-4 and CD40 ligand (CD40L) as specific B-cell activating signals. IgG was measured in supernatants from healthy human peripheral B cells cultured for 6 days. Percentage of cells that divided and IgG production were assessed under basal conditions (unstimulated), or stimulated with IL-4/CD40L alone (vehicle), or with IL-4/CD40L plus a 1:22 dilution of 80 U/mL stock of Acthar Gel.3,10

 

Acthar Gel has shown a direct immunomodulatory effect on monocyte-derived macrophages (MDMs), independent of cortisol release

In an in vitro study using human MDMs, Acthar Gel inhibited proinflammatory cytokines IL-6 and TNF-α, indicating an anti-inflammatory effect independent of cortisol release.5

 
Chart showing the effect of Acthar Gel on monocyte-derived macrophages (MDMs)
Chart showing the effect of Acthar Gel on monocyte-derived macrophages (MDMs)
 

§P<0.0001 versus vehicle-treated group.

This information is based on nonclinical data and the relationship to clinical benefit is unknown.

Study design: An in vitro study to explore the direct effects of Acthar Gel on human macrophages, focusing on induction of proinflammatory mediators following lipopolysaccharide (LPS) stimulation. Human blood derived monocytes were selected for CD14 expression using magnetic bead selection (MACS) and plated in presence of macrophage colony-stimulating factor (M-CSF). Cells were stimulated with LPS and incubated for a minimum of 24 hours with and without a 1:11 dilution of 80 U/mL stock of Acthar Gel. Cytokines were measured by enzyme-linked immunosorbent assay (ELISA).5

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INDICATION

Acthar® Gel (repository corticotropin injection) is indicated for severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation.

Important Safety information

Contraindications

  • Acthar should never be administered intravenously
  • Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar
  • Acthar is contraindicated where congenital infections are suspected in infants

INDICATION

Acthar® Gel (repository corticotropin injection) is indicated for severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation.

Important Safety information

Contraindications

  • Acthar should never be administered intravenously
  • Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar
  • Acthar is contraindicated where congenital infections are suspected in infants
  • Acthar is contraindicated in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction or sensitivity to proteins of porcine origins

Warnings and Precautions

  • The adverse effects of Acthar are related primarily to its steroidogenic effects
  • Acthar may increase susceptibility to new infection or reactivation of latent infections
  • Suppression of the hypothalamic-pituitary-axis (HPA) may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Adrenal insufficiency may be minimized by tapering of the dose when discontinuing treatment. During recovery of the adrenal gland patients should be protected from the stress (e.g. trauma or surgery) by the use of corticosteroids. Monitor patients for effects of HPA suppression after stopping treatment
  • Cushing’s syndrome may occur during therapy but generally resolves after therapy is stopped. Monitor patients for signs and symptoms
  • Acthar can cause elevation of blood pressure, salt and water retention, and hypokalemia. Blood pressure, sodium and potassium levels may need to be monitored
  • Acthar often acts by masking symptoms of other diseases/disorders. Monitor patients carefully during and for a period following discontinuation of therapy
  • Acthar can cause GI bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain gastrointestinal disorders. Monitor for signs of bleeding
  • Acthar may be associated with central nervous system effects ranging from euphoria, insomnia, irritability, mood swings, personality changes, and severe depression, and psychosis. Existing conditions may be aggravated
  • Patients with comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar in patients with diabetes and myasthenia gravis
  • Prolonged use of Acthar may produce cataracts, glaucoma and secondary ocular infections. Monitor for signs and symptoms
  • Acthar is immunogenic and prolonged administration of Acthar may increase the risk of hypersensitivity reactions. Neutralizing antibodies with chronic administration may lead to loss of endogenous ACTH activity
  • There is an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver
  • Long-term use may have negative effects on growth and physical development in children. Monitor pediatric patients
  • Decrease in bone density may occur. Bone density should be monitored for patients on long-term therapy
  • Pregnancy Class C: Acthar has been shown to have an embryocidal effect and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Adverse Reactions

  • Common adverse reactions for Acthar are similar to those of corticosteroids and include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite and weight gain
  • Specific adverse reactions reported in IS clinical trials in infants and children under 2 years of age included: infection, hypertension, irritability, Cushingoid symptoms, constipation, diarrhea, vomiting, pyrexia, weight gain, increased appetite, decreased appetite, nasal congestion, acne, rash, and cardiac hypertrophy. Convulsions were also reported, but these may actually be occurring because some IS patients progress to other forms of seizures and IS sometimes mask other seizures, which become visible once the clinical spasms from IS resolve

Other adverse events reported are included in the full Prescribing Information.

Please see full Prescribing Information.